This is a revised application for a K24 Midcareer Investigator Award in aging and Alzheimer's disease (AD) patient-oriented research. The candidate, Reisa A. Sperling, M.D. M.MSc., is an Associate Professor of Neurology at Harvard Medical School with a strong early track record as a productive clinical investigator and research mentor. The overarching aims of the candidate's research program are to: 1) elucidate the neural underpinnings of memory impairment in aging and early AD, 2) link the pathophysiological process of AD to the early clinical manifestations, and 3) develop sensitive imaging markers to track the progression of AD in the preclinical stages, enabling earlier intervention with disease-modifying treatments. The candidate has several ongoing NIH and foundation-funded multimodality imaging research projects in MCI and early AD, as well as a pending Program Project on aging and amyloid, which was recently very favorably reviewed. The applicant will use her funded research as a platform for the mentorship of new patient-oriented investigators and to promote a multidisciplinary research approach to the study of cognitive aging and early AD. The applicant's mentees will have the opportunity to train in functional, structural, and molecular imaging techniques, cognitive neuroscience, neuropsychological assessment of early dementia, biostatistics, and epidemiological aspects of longitudinal study design as they apply to aging and AD patient research, drawing expertise from an outstanding group of collaborators. Trainees will also be able to participate in research seminars, statistical training and imaging workshops provided by T32 and other training grants, career development and grant- writing workshops as part of the newly funded CTSA at Harvard, and didactic course work at Brigham and Women's Hospital, Massachusetts General Hospital, Massachusetts Institute of Technology, and the Harvard School of Public Health. The candidate herself will acquire additional expertise in advanced statistical and epidemiological methodology related to her ongoing research, and will expand her research into resting functional connectivity techniques as part of new research proposed for the K24 award. The K24 will be instrumental in advancing the candidate's research career in neuroimaging of early AD, and in protecting her time to mentor a new generation of investigators committed to AD patient-oriented research. PUBLIC HEALTH RELEVANCE: The applicant's research program seeks to understand the cause of memory problems in older individuals, to develop imaging tools to detect the earliest signs of Alzheimer's disease (AD), and to use these imaging tools to find effective treatments for AD. The applicant will use the K24 award to expand her imaging research program and to train new investigators for clinical research careers in patient-oriented AD research.